The major goal of this work is to understand the mechanism by which members of the Bcl-2 family regulate oncogenesis. The Bcl-2 family of proteins can be divided into two main classes: A) those that promote cell death (Bax, Bak, etc), and those that prevent it (Bcl-2, Bcl-xL, etc). An enabling characteristic of cancer cells that allows them to survive is their ability to evade cell death pathways by the upregulation of anti-apoptotic proteins like Bcl-2. Previous studies in our laboratory employing transgenic mouse models expressing pro-apoptotic Bax in T cells demonstrated an accelerated development of thymic lymphomas regardless of p53 status. Interestingly, other investigators have found Bcl-2 expression can prevent tumor formation. Taken together, these paradoxical findings suggest that Bax and Bcl-2 have novel functions in regulating oncogenesis. A hallmark of oncogenesis is genomic instability which has been observed in nearly all human malignancies and accelerates tumor formation. The current proposal will test the hypothesis that expression of Bax and Bcl-2 regulates genomic instability. We will test our hypothesis by 1) determining the rate on non-clonal chromosomal instability in transgenic mice expressing Bax and Bcl-2, and 2) the rate of allele modification (HPRT, CAD) in in vitro models of Bax and Bcl-2 genomic instability. The results of these studies will contribute greater knowledge of how the Bcl-2 family can regulate genomic instability and apoptosis in transformed cells and will shed important insight into the biology of oncogenesis.